Impact of statin use on breast cancer recurrence and mortality before and after diagnosis: a systematic review and meta-analysis

Objective Breast cancer is one of the most common causes of death among women. Statins, typically used for cholesterol management, have been hypothesized to reduce recurrence and mortality rates in breast cancer. However, this association remains a subject of debate. This study evaluates the potential impact of statins on breast cancer recurrence and mortality. Methods A comprehensive search was conducted in the PubMed, EMBASE, and Cochrane databases for articles published up to June 2023. These articles examined the effect of statins on breast cancer recurrence and mortality both before and after diagnosis. The analysis was performed using random-effects models, calculating pooled hazard ratios (HR) and their 95% confidence intervals (CI). Results A total of 31 cohort studies, involving 261,834 female breast cancer patients, were included in this analysis. It was found that statin use prior to diagnosis was associated with a decrease in overall mortality (HR, 0.8; 95% CI, 0.69–0.93; I2 = 77.6%; P = 0.001) and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67–0.87; I2 = 72.7%; P = 0.005). Additionally, statin use after diagnosis was observed to reduce the recurrence of breast cancer (HR, 0.71; 95% CI, 0.61–0.82; I2 = 60%; P = 0.003), overall mortality (HR, 0.81; 95% CI, 0.70–0.92; I2 = 80.7%; P < 0.001), and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67–0.86; I2 = 74.5%; P < 0.001). Conclusions The findings of this study indicate that statin usage, both before and after breast cancer diagnosis, may be associated with reduced risks of overall and breast cancer-specific mortality, as well as lower recurrence rates.


Introduction
Breast cancer remains a major health issue for women worldwide.It is a leading cause of cancer-related deaths (1,2), representing a quarter of all female cancer fatalities.In America, it ranks second only to lung cancer in terms of mortality rates (3,4).While developed countries have seen a decrease in breast cancer incidence and improved outcomes, the situation is worsening in developing nations (5) due to limited treatment options.This highlights the urgent need for new and effective treatments.
Statins, primarily prescribed for treating dyslipidemia to reduce the risk of atherosclerosis and cardiovascular events (6,7), are now increasingly being explored for their potential anti-cancer properties, extending beyond their well-known cardiovascular benefits (8,9).Initial studies suggest that statins may be effective in a variety of cancers (10), potentially by inhibiting cell proliferation and inducing apoptosis (11,12).The efficacy of statins appears to depend on their lipophilicity, dosage, and duration of treatment (10).However, due to patient diversity, there are discrepancies between laboratory studies and clinical data.Some studies have indicated a correlation between statin use and reduced breast cancer mortality (13-15), while others have found no such association (16)(17)(18).This study, therefore, aims to clarify the relationship between statin use and the risk of mortality or recurrence in women with breast cancer.

Methods
This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Search strategy and inclusion criteria
An extensive search was performed in the PubMed, EMBASE, and Cochrane CENTRAL databases for studies published up to 1 June, 2023.A combination of MeSH/Emtree terms and title/abstract keywords was used, focusing on "statins" and "breast cancer" (detailed in Stable 1).Included studies met these criteria: (1) involved adult patients diagnosed with breast cancer; (2) compared groups with and without statin use; (3) examined the relationship between statins and breast cancer mortality or recurrence; (4) provided detailed data on hazard ratios (HR) and 95% confidence intervals (CI) for outcomes such as recurrence, breast cancer-specific mortality, and all-cause mortality; and (5) were observational studies Flowchart of selecting studies for review.written in English.Exclusions were made for case reports, reviews, and preprints (search process illustrated in Figure 1).

Data extraction
Key information was extracted from selected studies, including the first author, publication year, study methodology, duration of follow-up, sample size, average age of participants, details of the statin intervention, and study outcomes.

Statistical analysis
The data for this meta-analysis were processed using STATA 12.0 software.To assess the impact of statins on breast cancer prognosis, HR and 95% CI from selected studies were extracted.Study variations were evaluated using the Q test and I 2 index.A Pvalue less than 0.05 and I 2 greater than 50% indicated significant heterogeneity, prompting the use of random-effects models for combined outcomes.Additionally, sensitivity analysis, Egger's test, and funnel plots were employed to assess the robustness and potential publication bias of the findings.

Discussion
This meta-analysis synthesized data from 31 studies involving 2,611,014 women diagnosed with breast cancer.It focused on assessing the impact of statins on the risk of overall mortality, breast cancer-specific mortality, and the recurrence of breast cancer.Our findings suggest a beneficial effect of statins, both prior to and after diagnosis, in reducing overall mortality, breast cancer-specific mortality, and the recurrence of the disease.These results are in line with a previous study (44) that reviewed 23 articles involving 178,712 breast cancer patients, which also suggested that statin use could decrease overall mortality, disease-induced mortality, and recurrence in women with breast cancer.However, the earlier metaanalysis (44) was limited to post-diagnosis statin use and did not include data on pre-diagnosis use.Other research (45) has indicated that statins may reduce disease-induced mortality and recurrence in breast cancer patients, but did not differentiate between pre-and post-diagnosis use of statins, and found no significant impact on the risk of developing breast cancer.Additionally, a study (46) involving seven studies and 197,048 women with breast cancer indicated that statins might reduce both disease-induced and overall mortality.In addition, a randomized controlled study (47) showed that statin use after diagnosis was associated with a reduction in all-cause mortality (HR, 1.16; 95% CI, 0.7-1.91).Furthermore, there is evidence (48) suggesting an enhanced effect on breast cancer reduction when pitavastatin is used alongside neoadjuvant chemotherapy protocols.
Ongoing research is examining the mechanisms through which statins may decrease mortality in breast cancer patients.The mevalonate pathway, a common feature in cancerous lesions, is upregulated and can be inhibited by statins, exerting an anti-cancer effect.Statins also have an association with ferroptosis (49) and can Forest plot of the HR of this meta-analysis for the overall mortality between statin and non-statin use in patients with prior to breast cancer.

FIGURE 3
Forest plot of the HR of this meta-analysis for breast cancer-specific mortality in patients with prior to diagnosis breast cancer.
impair autophagy flux, leading to breast cancer cell death via the ERK1/2 and Akt pathways (50,51).Preclinical studies suggest that statins can reduce the activity of breast cancer cells, limit their proliferation, and induce apoptosis (52).Atorvastatin may enhance antitumor immunity by inhibiting extracellular vesicles programmed death-ligand 1 (PD-L1) (53).Furthermore, altering cholesterol abundance in cancer cells could affect cellular membrane fluidity and signal transduction, influencing cancer progression (54).The role of statins in three estrogen receptorpositive cancers (breast, endometrial, and ovarian) is currently under investigation, with studies reporting a beneficial role in reducing incidence and mortality (55).In patients with estrogendependent breast cancer, post-diagnostic statin use has been linked to reduced cancer-specific mortality (56), potentially by disrupting hormone receptor-related pathways (57).The combination of metformin and simvastatin is reported to enhance the expression Forest plot of the HR of this meta-analysis for breast cancer recurrence in patients with post-diagnosis breast cancer.Forest plot of the HR of this meta-analysis for the overall mortality between statin and non-statin use in patients with post-diagnosis breast cancer.
of prolyl hydroxylase 2, decreasing hypoxia-inducible factor 1a expression induced in endothelin 1, leading to more effective antiangiogenic and anti-cancer effects (58).
This meta-analysis has some limitations.Firstly, the specific types of statins used were not clearly detailed in the original studies, and different types of statins might yield different results.Secondly, while we included studies focusing on the effect of statins on the prognosis of breast cancer patients, the dosage of statins varied across these studies.Lastly, the studies included were observational, which may introduce more confounding bias and loss of follow-up.

Conclusions
In conclusion, the results of this meta-analysis indicate that the use of statins may beneficially impact the recurrence of breast cancer, as well as reduce all-cause mortality and breast cancer-specific mortality, Forest plot of the HR of this meta-analysis for breast cancer-specific mortality prior to diagnosis in patients with post-diagnosis breast cancer.Forest plot of the HR of this meta-analysis of statins for more than a year after diagnosis for breast cancer recurrence in patients with breast cancer.
irrespective of whether statins are used before or after a breast cancer diagnosis.However, these findings underscore the necessity for additional high-quality research to more definitively ascertain the effects of statins on the prognosis of women with breast cancer.

TABLE 1
Characteristics of the included studies in the meta-analysis of statin vs non-statin use in adult breast cancer patients.